The long-term objectives of this research proposal is to dissect the molecular and cellular mechanisms underlying the synaptic plasticity, long term potentiation (LTP) and long-term depression (LTD), in the hippocampus and/or cerebellum of the mammalian brain, and to examine the role of such plasticity as mechanisms for learning and memory, and for kindling, an animal model of epilepsy. To this end, a new genetic approach based on gene targeting in embryonic stem (ES) cells has been introduced. Four distinct strains of mutant mice with a non revertible mutation in one of four different enzymes whose functions are thought to be involved in at least some forms of synaptic plasticity will be analyzed or constructed and analyzed by a variety of methods including immunocytochemistry, in vitro and in vivo, electrophysiology, and behavioral paradigms such as Morris water maze fear conditioning, eyeblink conditioning, and epileptic behavior. These enzymes are the alpha isoform of Ca2+/calmodulin-dependent protein kinase type II, gamma and Beta isoforms of protein kinase C, and heme-oxygenase II required for the synthesis of carbon monoxide (CO) which may have a retrograde messenger activity in LTP. In addition, this application proposes to develop new methods with which a genetic deletion in a specific protein of interest can be induced in grown up animals or restricted to certain subregions of the brain. These methods are expected to expand substantially the power of the genetic approach in the analysis of brain functions. This proposal will help understand the fundamental molecular and cellular mechanisms for learning and memory as well as for epilepsy in mice. Information obtained is expected to be useful for the development of diagnostic and therapeutic methods for neurological diseases such as Alzheimer's disease and epilepsy.